Anastrozole-mediated modulation of mitochondrial activity by inhibition of mitochondrial permeability transition pore opening: an initial perspective

The mitochondrial permeability transition pore (mtPTP) plays a vital role in altering the structure and function of mitochondria. Cyclophilin D (CypD) is a mitochondrial protein that regulates mtPTP function and a known drug target for therapeutic studies involving mitochondria. While the effect of...

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Published in:Journal of biomolecular structure & dynamics 2023, Vol.41 (23), p.14063-14079
Main Authors: Kumar, Somesh, Choudhary, Neha, Faruq, Mohammed, Kumar, Arun, Saran, Ravindra K, Indercanti, Prem Kumar, Singh, Vikram, Sait, Haseena, Jaitley, Sunita, Valis, Martin, Kuca, Kamil, Polipalli, Sunil K, Kumar, Manoj, Singh, Tejveer, Suravajhala, Prashanth, Sharma, Rohit, Kapoor, Seema
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - metabolism
Anastrozole
Anastrozole - metabolism
Anastrozole - pharmacology
binding sites
Cyclophilins - genetics
Cyclophilins - metabolism
docking complexes
Humans
Leukocytes, Mononuclear - metabolism
MD simulation
Mitochondria - metabolism
Mitochondrial Diseases - metabolism
mitochondrial disorders
Mitochondrial Membrane Transport Proteins - metabolism
Mitochondrial Membrane Transport Proteins - pharmacology
mitochondrial permeability transition pore
Mitochondrial Permeability Transition Pore - metabolism
Mitochondrial Permeability Transition Pore - pharmacology
molecular docking
Peptidyl-Prolyl Isomerase F
protein targets
structural modelling
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Summary:The mitochondrial permeability transition pore (mtPTP) plays a vital role in altering the structure and function of mitochondria. Cyclophilin D (CypD) is a mitochondrial protein that regulates mtPTP function and a known drug target for therapeutic studies involving mitochondria. While the effect of aromatase inhibition on the mtPTP has been studied previously, the effect of anastrozole on the mtPTP has not been completely elucidated. The role of anastrozole in modulating the mtPTP was evaluated by docking, molecular dynamics and network-guided studies using human CypD data. The peripheral blood mononuclear cells (PBMCs) of patients with mitochondrial disorders and healthy controls were treated with anastrozole and evaluated for mitochondrial permeability transition pore (mtPTP) function and apoptosis using a flow cytometer. Spectrophotometry was employed for estimating total ATP levels. The anastrozole-CypD complex is more stable than cyclosporin A (CsA)-CypD. Anastrozole performed better than cyclosporine in inhibiting mtPTP. Additional effects included inducing mitochondrial membrane depolarization and a reduction in mitochondrial swelling and superoxide generation, intrinsic caspase-3 activity and cellular apoptosis, along with an increase in ATP levels. Anastrozole may serve as a potential therapeutic agent for mitochondrial disorders and ameliorate the clinical phenotype by regulating the activity of mtPTP. However, further studies are required to substantiate our preliminary findings. Communicated by Ramaswamy H. Sarma
ISSN:0739-1102
1538-0254
DOI:10.1080/07391102.2023.2176927